Aromatic azomethines of n-thiazolinyl and n-thiazinyl indoles

ABSTRACT

Novel indoles having a thiazolinyl or thiazinyl group in the 1position and an azomethine group in either the 5- or the 6position are useful as anti-inflammatory agents.

United States Patent [191 Narayanan et al.

[ Dec. 1 0, 1974 AROMATIC AZOMETHINES OF N-THIAZOLINYL AND N-THIAZINYL INDOLES Inventors: Venkatachala L. Narayanan,

Highstown; Rudiger D. Haugwitz, Titusville, both of N].

Assignee: E. R. Squibb & Sons, Inc., Princeton,

Filed: Apr. 30, 1973 Appl. No.: 356,009

US. Cl 260/240 G, 260/243 R, 260/306.7,

424/246, 424/270 Int. Cl C09b 23/00 Field of Search 260/240 G, 243 R Primary ExaminerJohn D. Randolph Attorney, Agent, or Firm-Lawrence S. Levinson;

Merle J. Smith; Donald J. Barrack Novel indoles having a thiazolinyl or thiazinyl group in the l-position and an azomethine group in either the 5- or the 6-position are useful as anti-inflammatory agents.

ABSTRACT 5 Claims, N0 Drawings AROMATIC AZOMETHINES OF N-THIAZOLINYL AND N-THIAZINYL INDOLES SUMMARY OF THE INVENTION lndoles having a thiazolinyl or thiazinyl group in the I-position and an azomethine group in either the 5- or the 6-position are anti-inflammatory agents. Azomethines of N-thiazolinyl and N-thiazinyl indoles having the structure:

are preferred. The azomethine group is attached to the indole in either the 5- or the 6-position. In formula I and throughout the specification the symbols are as defined below.

R is phenyl or substituted phenyl. The expression substituted phenyl includes phenyl groups which are substituted in one, two, or three positions with from 1 to 3 of the following groups: halo, nitro, lower alkyl, lower alkoxy, hydroxy, monoor di(lower alkyl)amino, amido, acetamido, cyano, carboxy, benzyloxy, or trifluoromethyl.

R is hydrogen, lower alkyl, phenyl, (CI-I 1COOR cyano, halo, or di(lower alkyl)amino lower alkyl, R, is hydrogen, lower alkyl or phenyl; and n is to 5.

R is hydrogen, lower alkyl, phenyl or (Cl-I 1 COOR5.

The group represents a or 6-membered ring containing three or four carbon atoms, respectively, wherein the two or three carbon atoms not shown may include a substituent as shown. R is hydrogen, lower alkyl or phenyl.

The term lower alkyl as employed herein includes both straight and branched chain radicals of up to eight carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, tbutyl, n-pentyl, 4,4-dimethyl' pentyl, octyl and the like.

The term halo includes fluorine, bromine, chlorine and iodine.

DETAILED DESCRIPTION OF THE INVENTION Indoles containing a 2-thiazolin-2-yl or 2-thiazin-2-yl group in the l-position and an azomethine group of the formula R HC=N in either the 5- or the 6-position are anti-inflammatory agents.

Compounds of formula I are preferred and compounds of formula I wherein R R and R are hydrogen are especially preferred. 7

The azomethines of N-thiazolinyl and N-thiazinyl indoles of this invention are synthesized from indoles having the structure:

wherein the amino group is in either the 5- or the 6- position. The indole of formula II is reacted with an aldehyde having the formula:

R R1 CH (I It) The molar ratio of indole of formula II to the aldehyde of formula III is from 1:1 to 1:50. The reaction is carried out at a temperature of from to 200C for a period of about 5 minutes to about 24 hours. A protic solvent (e.g., ethanol, 3-methylbutanol, etc.) or an aprotic solvent (e.g., nitrobenzene, dimethylsulfoxide, dimethylformamide, etc.) may be used to run the condensation reaction, or if desired, an excess of the aldehyde reactant may be used in lieu of solvent. If desired, an acid catalyst (e.g., a conventional acid such as hydrochloric, sulfuric or benzenesulfonic acid or a Lewis acid such as ZnCl or POClmay be used.

Alternatively, the compounds of this invention may be formed by refluxing an amine of formula II with an aldehyde of formula III. The use of an azeotro'ping agent (e.g., benzene) permits separation of the water formed during the reaction.

Exemplary of the aromatic aldehydes which may be used to prepare the compounds of formula I are:

p-acetamidobenzaldehyde, 0- m-, or p-anisaldehyde, benzaldehyde, 3- or 4-benzyloxybenzaldehyde, 3-(or 4-)benzyloxy-4-(or 3-)methoxybenzaldehyde, 5-bromo-o-anisaldehyde, 2-(or 3- or 4-)bromobenzaldehyde, 5-bromosalicaldehyde, 5-bromovanillin, 5-(or 6-)bromoveratraldehyde, 2-(or 4-)carboxybenzaldehyde, 2-(or 3- or 4-)chlorobenzaldehyde, 2-chloro-4-dimethylaminobenzaldehyde, 2-chloro-6-fluorobenzaldehyde, 3-chloro-4-hydroXy-5-methoxybenzaldehyde, 2-chloro-5-(or 6-)nitrobenzaldehyde, 4-chloro-3-nitrobenzaldehyde, 5-chloro-2-nitrobenzaldehyde, 3-(or 4-)cyanobenzaldehyde, 3,4-dibenzyloxybenzaldehyde, 3,5-dibromosalicylaldehyde, 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 2,4-(or 2,6- or 3,4- or 3,5-)dichlorobenzaldehyde, 4-(diethylamino)-benzaldehyde, 2,5-(or 3,4-)dihydroxybenzaldehyde, 2,4-(or 2,5- or 3,4- or 3,5-)dimethoxybenzaldehyde, 4,6-dimethoxysalicylaldehyde, p-dimethy]aminobenzaldehyde, 2,3-(or 2,5-)dimethyl-p-anisaldehyde, 2,4-(or 2,5-)dimethylbenzaldehyde, 2,4-(or 2,6- )dinitrobenzaldehyde, 0- or p-ethoxybenzaldehyde, 3-ethoxy-4-hydroxybenzaldehyde,

4-ethoxy-3-methoxybenzaldehyde,

3-ethoxysalicylaldehyde,

-, m-, or p-fluorobenzaldehyde,

4-fluoro-2-nitrobenzaldehyde,

-formylsalicylic acid,

3-hydroxy-p-anisaldehyde,

3-(or 4-)hydroxybenzaldehyde,

2-hydroxy-4-(or 5-)methoxybenzaldehyde,

3-hydroxy-4-nitrobenzaldehyde,

4-hydroxy-3-nitrobenzaldehyde, 5-hydroxy-2-nitrobenzaldehyde,

5-iodovanillin,

3-rnethyl-p-anisaldehyde,

o-, m-, or p-nitrobenzaldehyde,

S-nitrovanillin,

6-nitroveratraldehyde,

salicylaldehyde,

syringaldehyde,

o-, m-, or p-tolualdehyde,

2,4,6-triethoxybenzaldehyde,

4-trifluoromethylbenzaldehyde,

2,3,4-(or 2,4,5-, or 2,4,6-, or 3,4,5-)trimethoxybenzaldehyde,

2,4,6-trinitrobenzaldehyde,

vanillin,

o-vanillin.

Preparation of the indoles of formula 11 is disclosed in copending Pat. application, Ser. No. 191,092, filed Oct. 20, 1971 now U.S. Pat. No. 3,755,316 issued Aug. 28, 1973, the disclosure of which is incorporated herein by reference.

Specifically, the 5- or the 6-aminoindoles of formula II are prepared from the corresponding 5- or 6- nitroindoles, i.e. indoles having the formula:

ried out at a pressure from 30 to psi for a period of 2 hours to 1 day.

The compounds of this invention are used to treat inflammation in a mammalian species, e.g., rats, dogs, cats, monkeys, etc. Joint tenderness and stiffness (in conditions such as rheumatoid arthritis) are relieved by the above described indoles.

The indoles of this invention may be formulated for use as anti-inflammatory agents according to accepted pharmaceutical practice in oral dosage forms such tablets, capsules, elixirs, or powders or in injectable form.

The compounds of this invention may be administered in amounts at about mg/70 kg/day to 2 g/70 kg/day, preferably 100 mg/7() kg/day to 1 g/70 kg/day. The following examples further illustrate the invention.

Example 1 5-[(o-Hydroxybenzylidene)amino]-1-(2-thiazolin-2- yl)indole a. 5-Amino-N-(2-thiazolin-2-yl)indole 4.0 g of 5-Nitro-N-(2-thiazolin-2-yl)indole (0.016 mole) is dissolved in 100 ml. of tetrahydrofuran and approximately one teaspoon of Raney nickel catalyst is added. The mixture is then hydrogenated at 65 psi over a period of 16 hours. The Raney nickel is removed and a thin-layer chromatograph run on the THF solution indicates complete reduction (5% MeOH/CHCl;,-silica gel). 5-Amino-N-(2thiazolin-2-yl)-indole is recovered from the solution.

b. 5-[(o-Hydroxybenzylidene)aminol- 1 Z-thiazolin- Z-yllindole 5-Amino-N-(2-thiazolin-2-yl)indole (2.0 g., 0.0091 mole) is dissolved in 100 ml. of absolute ethanol at room temperature. Salicylaldehyde (1.2 g., 0.01 mole) is added and the mixture is refluxed for 2 hours, cooled to room temperature, and the precipitated product collected. Crystallization from a mixture of methanol and dimethylformamide (3:1 1 yields 2.3 g. of 5-[(ohydroxybenzylidene)amino]-1-( 2-thiazolin-2- yl)indole, melting point 106-108C.

Analysis for C, H, N OS Calcd: C, 67.27; H. 4.81. N. 13.07.

Found: C, 67.17; H. 5.01; N, 13.18.

Examples 2 26 Following the procedure of Example la, but substituting the nitroindole of column 1 for 5-nitroN-(2- thiazolin-2yl)-indole, the corresponding aminoindole is obtained. The aminoindole is reacted with the aldehyde of column 2, following the procedure of Example 112, to yield the product of column 3.

m cEs oo MO QOHMMmO H H V EHHOU mooou m What is claimed is: 1. An indole having the formula wherein the azomethine group is attached to the indole in the or the 6-position; R is phenyl or phenyl substituted in l, 2, or 3 positions with one or more groups selected from the group consisting of halo, nitro, lower alkyl, lower alkoxy, hydroxy, monoor di(lower alkyl- )amino, amido, acetamido, cyano, carboxy, benzyloxy, and trifluoromethyl; R is selected from the group consisting of hydrogen, lower alkyl, phenyl, (CH "ICOOR5, cyano, halo, and di(lower alkyl)amino lower alkyl; R is selected from the group consisting of hydrogen, lower alkyl, phenyl, and (CH ),.1COOR R and R are each selected from the group consisting of hydrogen, lower alkyl, and phenyl; n is 0, l, 2, 3, 4 or 5;

a 5- or 6-membered ring containing 3 or 4 carbon atoms respectively.

2. An indole in accordance with claim 1 wherein R R and R are each hydrogen.

3. An indole in accordance with claim 1 having the formula UNiTED STATES PATENT OFFICE CERTXFECATE 0F 'CORREC'HGN Inventor s Venkatachala L. Narayanan and Rudiger D. Haugwitz It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 18, :lirie 1, Claim 1, please insert the word: is

at the beginning of the line.

Signed and sealed this 11th day of February 1975.

and Trademarks (SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON t t Attesting Officer Commissioner of Pa en s FORM PO-105O (10-69) USCOMM-DC 60376-P69 U.S.'GOVERN MENT PRINTING OFFICE: I989 O-3G6-334. 

1. AN INDOLE HAVING THE FORMULA
 2. An indole in accordance with claim 1 wherein R2, R3, and R4 are each hydrogen.
 3. An indole in accordance with claim 1 having the formula
 4. An indole in accordance with claim 1 having the formula
 5. An indole in accordance with claim 3 having the name 5-((o-hYdroxybenzylidene)amino)-1-(2-thiazolin-2-yl)-indole. 